Ashrafian Houman, Horowitz John D, Frenneaux Michael P
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Cardiovasc Drug Rev. 2007 Spring;25(1):76-97. doi: 10.1111/j.1527-3466.2007.00006.x.
Perhexiline, 2-(2,2-dicyclohexylethyl)piperidine, was originally developed as an anti-anginal drug in the 1970s. Despite its success, its use diminished due to the occurrence of poorly understood side effects including neurotoxicity and hepatotoxicity in a small proportion of patients. Recently, perhexiline's mechanism of action and the molecular basis of its toxicity have been elucidated. Perhexiline reduces fatty acid metabolism through the inhibition of carnitine palmitoyltransferase, the enzyme responsible for mitochondrial uptake of long-chain fatty acids. The corresponding shift to greater carbohydrate utilization increases myocardial efficiency (work done per unit oxygen consumption) and this oxygen-sparing effect explains its antianginal efficacy. Perhexiline's side effects are attributable to high plasma concentrations occurring with standard doses in patients with impaired metabolism due to CYP2D6 mutations. Accordingly, dose modification in these poorly metabolizing patients identified through therapeutic plasma monitoring can eliminate any significant side effects. Herein we detail perhexiline's pharmacology with particular emphasis on its mechanism of action and its side effects. We discuss how therapeutic plasma monitoring has led to perhexiline's safe reintroduction into clinical practice and how recent clinical data attesting to its safety and remarkable efficacy led to a renaissance in its use in both refractory angina and chronic heart failure. Finally, we discuss the application of pharmacogenetics in combination with therapeutic plasma monitoring to potentially broaden perhexiline's use in heart failure, aortic stenosis, and other cardiac conditions.
哌克昔林，即2-(2,2-二环己基乙基)哌啶，最初是在20世纪70年代作为一种抗心绞痛药物开发的。尽管取得了成功，但由于一小部分患者出现了包括神经毒性和肝毒性在内的难以理解的副作用，其使用量减少。最近，哌克昔林的作用机制及其毒性的分子基础已被阐明。哌克昔林通过抑制肉碱棕榈酰转移酶来减少脂肪酸代谢，该酶负责线粒体摄取长链脂肪酸。相应地向更多碳水化合物利用的转变提高了心肌效率（每单位氧消耗所做的功），这种氧节约效应解释了其抗心绞痛疗效。哌克昔林的副作用归因于因CYP2D6突变导致代谢受损的患者在使用标准剂量时出现的高血浆浓度。因此，通过治疗性血浆监测识别出这些代谢不良的患者后调整剂量，可以消除任何明显的副作用。在此我们详细阐述哌克昔林的药理学，特别强调其作用机制和副作用。我们讨论治疗性血浆监测如何使哌克昔林安全地重新引入临床实践，以及最近证明其安全性和显著疗效的临床数据如何导致其在难治性心绞痛和慢性心力衰竭中的使用复兴。最后，我们讨论药物遗传学与治疗性血浆监测相结合的应用，以潜在地扩大哌克昔林在心力衰竭、主动脉瓣狭窄和其他心脏疾病中的应用。
